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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

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August 14, 2013

Another T-Cell Advance Against Cancer

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Posted by Derek

The technique of using engineered T cells against cancerous cells may be about to explode ever more than it has already. One of the hardest parts of getting this process scaled up has been the need to extract each patient's own T cells and reprogram them. But in a new report in Nature Biotechnology, a team at Sloan-Kettering shows that they can raise cells of this type from stem cells, which were themselves derived from T lymphocytes from another healthy donor. As The Scientist puts it:

Sadelain’s team isolated T cells from the peripheral blood of a healthy female donor and reprogrammed them into stem cells. The researchers then used disabled retroviruses to transfer to the stem cells the gene that codes for a chimeric antigen receptor (CAR) for the antigen CD19, a protein expressed by a different type of immune cell—B cells—that can turn malignant in some types of cancer, such as leukemia. The receptor for CD19 allows the T cells to track down and kill the rogue B cells. Finally, the researchers induced the CAR-modified stem cells to re-acquire many of their original T cell properties, and then replicated the cells 1,000-fold.

“By combining the CAR technology with the iPS technology, we can make T cells that recognize X, Y, or Z,” said Sadelain. “There’s flexibility here for redirecting their specificity towards anything that you want.”

You'll note the qualifications in that extract. The cells that are produced in this manner aren't quite the same as the ones you'd get by re-engineering a person's own T-cells. We may have to call them "T-like" cells or something, but in a mouse lymphoma model, they most certainly seem to do the job that you want them to. It's going to be harder to get these to the point of trying them out in humans, since they're a new variety of cell entirely, but (on the other hand) the patients you'd try this in are not long for this world and are, in many cases, understandably willing to try whatever might work.

Time to pull the camera back a bit. It's early yet, but these engineered T-cell approaches are very impressive. This work, if it holds up, will make them a great easier to implement. No doubt, at this moment, there are Great Specific Antigen Searches underway to see what other varieties of cancer might respond to this technique. And this, remember, is not the only immunological approach that's showing promise, although it must be the most dramatic.

So. . .we have to consider a real possibility that the whole cancer-therapy landscape could be reshaped over the next decade or two. Immunology has the potential to disrupt the whole field, which is fine by me, since it could certainly use some disruption, given the state of the art. Will we look back, though, and see an era where small-molecule therapies gave people an extra month here, an extra month there, followed by one where harnessing the immune system meant sweeping many forms of cancer off the board entirely? Speed the day, I'd say - but if you're working on those small-molecule therapies, you should keep up with these developments. It's not time to consider another line of research, not yet. But the chances of having to do this, at some point, are not zero. Not any more.

Comments (20) + TrackBacks (0) | Category: Biological News | Cancer


COMMENTS

1. barry on August 14, 2013 8:11 AM writes...

the antibody-with-a-small-molecule-warhead people have been looking for high-fidelity cell-surface markers for cancers for years. Turns out that they're very rare. Perhaps any proto-cancer cell that displayed a distinctive cell-surface antigen gets eliminated by our immune systems before we ever diagnose it?
As of 2013, the distinctive markers of cancer are still overwhelmingly intracellular. Until someone gets antibodies or TCRs into the cytosol, that's still the realm of small-molecule therapeutics.

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2. NMH on August 14, 2013 8:25 AM writes...

Just think of the cost of this procedure. I'm sure american hospitals would love to add this to their repitiore of expensive techniques that they can charge at a ridiculous rate, even more than the huge expensive that the technique is by itself. The MD/MBA's hospital administrators must be drooling.

Frankly, if I get cancer, just give me valium. I don't want the greedy hospital to take my money.

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3. immunotherapy advocate on August 14, 2013 9:03 AM writes...

@barry

Agree with you in part, but rather than continuing to bet on small molecules that offer only marginal survival benefit as Derek rightly points out in his post, I'm betting on therapies such as anti-PD-1 that stimulate the immune response that's already there, but being actively suppressed by the tumor. In contrast to a CAR, doesn't invoke need for tumor-selective antigen, market-validated (mAb) technology, no Frankensteinian manufacturing process and, most importantly, provides for durable response in contrast to small-molecule therapies.

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4. Joel on August 14, 2013 10:59 AM writes...

Hi Derek- your italics tags don't work in your RSS feed. Might want to get someone to fix that!

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5. Anonymous on August 14, 2013 11:36 AM writes...

It's not a question of either, or. Cancer is essentially an extensive set of different and highly complex diseases, and to successfully treat many of these, a combination approach will most certainly be required. That includes small-molecules, immunotherapy, and anti-bodies. However, I do agree with Derek that the immunological approach could potentially be a huge game changer indeed. I'm personally excited to see how it all plays out.

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6. qetzal on August 14, 2013 11:47 AM writes...

@barry,

Actually, a key property of T cell receptors is that they recognize processed peptides from intracellular proteins that are then displayed on the cell surface by HLA molecules. Recognition of peptides from mutated intracellular tumor proteins is probably the basis for the apparent efficacy of Tumor Infiltrating Lymphocyte therapy for melanoma (a la Steve Rosenberg at NIH).

CARs, on the other hand, are indeed restricted to conventional cell surface markers, since they use antibody Fabs as the basis for their recognition. CD19 looks like quite a good target for CARs against leukemias and lymphomas, but I agree that it's unclear how many other good CAR targets there will be for other tumor types.

Things like anti-PD-1 are pretty hot right now, but I've seen some data suggesting that combos with T cell therapies can be even better.

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7. immunotherapy advocate on August 14, 2013 3:28 PM writes...

@qetzal,

See Immunocore's ImmTACs for (redirected) T-cell therapy against intracellularly-derived MHC-peptide complex.

Even if one transfected T-cells with ImmTACs, one would still be directing one's therapy against a single antigen barring (problematic) polyclonal/cocktail approaches. By contrast, a patient's immune system is obviously capable of responding to the full spectrum of immunogenic stimuli a given tumor might present.

Additionally, T-cell therapies are going to suffer from much more severe toxicity profiles than agents such as anti-PD-1, as a general rule, excepting "easy" targets such as CD-19.

That said, I agree that combinations will be the answer for most cancer patients; combinations of mAbs, small molecules, T-cell therapies, vaccines - whatever it takes that is acceptably tolerable. I simply believe agents like anti-PD-1 to be foundational and probably of much broader utility than CARs and the like.

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8. qetzal on August 14, 2013 3:54 PM writes...

@immunotherapy advocate,

Agreed. My main point was that T cell and T cell receptor-based strategies aren't restricted to cell surface proteins (contra barry's comment). They work at the cell surface, but recognition is based on fragments of intracellular proteins.

Targeting a single T cell epitope is certainly a limitation, given the potential for tumor escape by epitope loss. But "polyclonal" approaches do exist. I gave the example of Rosenberg's TILs for melanoma, but there are other approaches as well.

There are other limitations, of course, not least the downregulation of HLA and the other tumor suppressive activities used by many tumors.

As you say, whatever works, in whatever combination, is what we should aim for.

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9. HFM on August 14, 2013 5:13 PM writes...

As I understand it...what #1 said. This therapy goes after immune cell cancers, which are a special case - there are dozens of subtypes distinguishable by surface markers. You can destroy any one of those subtypes with immunotherapy, getting rid of the cancer and leaving a mostly immunocompetent patient. It's awesome that this works, yes, but this is the easy case.

There might be some other cancers where wiping out the whole class of cells the cancer originated from is feasible. I've heard some speculations about melanoma - sure, you'll become a functional albino and probably go blind, but you won't die. But there are a lot more cancer types where you just can't.

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10. MadDog on August 14, 2013 6:15 PM writes...

It is no longer small molecule -vs- large molecule in this space. There are small molecules that are used to expand stem cell lines.

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11. Pennpenn on August 14, 2013 7:40 PM writes...

@ NMH- Yeah, because just dosing cancer patients with painkillers is totally going to help matters.

In fact, lets just stop medical science altogether, since it's obviously just a con to money from sick people!

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12. barry on August 15, 2013 10:12 AM writes...

it should be emphasized that the new paper directs the modified T-cells not against a cancer marker but against a tissue marker. cd19 just identifies B-cells, healthy or cancerous. Wiping out the patient's whole repertoire of B-cells if efficacious, and tolerated, but this is tissue-targetted therapy, not cancer-targetted therapy, removing the whole organ rather than the malignancy.

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13. immunotherapy advocate on August 15, 2013 11:08 AM writes...

@barry,

Yes, precisely. The need for a selective antigen will limit CAR-like applications to "liquid" tumor indications, by and large, where one can afford to wipe out entire tissues. That said, at least CARs are able to bypass tumor suppression in contrast to adoptive T-cell transfer approaches such as those being tested by Dr Rosenberg thereby potentially providing for durable responses.

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14. qetzal on August 15, 2013 11:41 AM writes...

Agreed - CARs target cell surface markers, are likely to attack any marker-positive cells regardless of whether they are normal or malignant, and bypass at least some tumor suppression activities. E.g., they don't depend on MHC presentation, so they aren't affected by tumor down-regulation of that. I'm not sure if there may be other suppression activities that still apply though.

As for TILs, if you're suggesting that they can't achieve durable response, I'm pretty sure Dr. Rosenberg and multiple others would disagree. See, e.g., here. Whether that approach has much commercial potential, or whether it has significant application outside of melanoma, I'm not so sure.

Disclosure: I have a professional interest in T cell therapies, but not currently in either CARs or TILs.

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15. immunotherapy advocate on August 15, 2013 12:38 PM writes...

qetzal,

It's my understanding that the rates of durable responses thought to have been observed in ACT trials haven't held up with time. Would appreciate clinical references if available.

Even if objective and durable response rates in melanoma are as stated, these are no better than for the best anti-PD-1 data with higher rates of adverse events.

So, why advocate for an extremely complex treatment regimen when an antibody or antibody-antibody/antibody-small molecule can do as well or maybe better with less tox?

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16. qetzal on August 15, 2013 2:36 PM writes...

I linked to a review in #14. That cites a number of recent clinical studies.

As far as I can see, durable responses with TILs in metastatic melanoma have actually improved over time. This is based partly on better lymphodepletion regimens, and partly on using a shorter culturing method that seems to give more potent T cells. At least three groups are claiming ORs in the 40-70% range: Rosenberg/NIH, Radvanyi/MD Anderson, and Schachter/Sheba Med Ctr Israel.

The caveat is that those RRs are for treated patients. Because of the time to prepare the cells, significant numbers of patients drop out before they can be treated. Thus, ITT analyses give worse numbers, though I've seen groups claiming that they're overcoming that problem as well.

I agree this is much more complicated than giving a mAb, and SAEs from the lymphodepletion are certainly a big issue. So, maybe TILs won't offer an advantage over anti-PD-1. I'm not as up to speed on that, to be honest. In any case, I wasn't trying to suggest that TILs were clearly superior. I was only arguing that, whatever their limitations, there's a lot of clinical evidence suggesting they probably do work in adv. melanoma.

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17. cliffintokyo on August 18, 2013 7:21 AM writes...

Nice commentary in the discussion on the state of the art in targeted cancer chemotherapy - good to see a quality scientific discussion here, guys!
Caveat: As Sir James Black once famously said, 'Don't believe everything that the pharmacologists tell you!'

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18. Anonymous on September 7, 2013 4:12 AM writes...

Its a very good idea. But again all I wonder is how the cost of this whole thing going to be like. It again seem to be a restriction towards curing cancer.

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19. Anonymous on September 14, 2013 11:54 AM writes...

interesting how some individuals are focused on cost. Current therapies such as Gleevec, Avastin, Herceptin, Zelboraf etc cost thousands and sometimes, hundreds of thousands of $$$$ for some patients during their lifetime. Drug development is expensive and small molecule oral inhibitors that cost pennies to manufacture cost >$5,000 per month.

we need innovation and not more me-too drugs.

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20. Mimi on November 14, 2013 9:24 AM writes...

I am thankful for this whatever the cost! I just lost my mother to cancer and would have loved to have had this available to save her! I welcome this procedure!!!!!! I have lost a cousin five years ago again it would have been welcomed! It's not about money it is about life!!!!!!

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